Unraveling the mechanisms of prostate carcinogenesis is a uniquely challenging task because of the histopathological and molecular heterogeneity and limited availability of human tumor tissue. Arguably the most significant stride in the past few years towards the understanding of the mechanisms involved in prostate carcinogenesis is the discovery that genetic alterations in the phosphoinositide 3-kinase (PI3K) pathway occur frequently and play a functional role in this disease. The major role of the Pathology core in this program project is to evaluate morphologically and molecularly murine tissues genetically engineered to express mutant PI3K genes and to the compare the findings with human prostate cancers. The aim is to dissect at the tissue level the alterations in this pathway relevant to human prostate carcinogenesis to ultimately implement novel therapeutic strategies based on targeting PI3K. The pathologic analysis will include evaluation of genetically engineered mice and of tissue recombination experiments, the analysis of PI3K signaling pathways in both murine and human cancers with activation-specific antibodies and nucleic acid probes, and the validation and assessment of novel therapeutic targets related to the PI3K pathway in human prostate cancer specimens. To address prostate cancer heterogeneity, state of the art techniques to simultaneously assess multiple PI3K gene products at the tissue level will be developed. This Core will work in close collaboration with the Project Investigators and with other Core Leaders to provide the following: i) histology services and standardized systematic morphologic consultative expertise in the pathologic evaluation of mouse and human prostate neoplasms;ii) infrastructure and technical expertise for a variety of molecular pathologic assays, including consultative services in the generation of tissue recombinants;ill) validation of molecular alterations in the PI3K pathway in mouse and human prostatic tissue specimens; and iv) development and implementation of highly innovative technologies that will greatly facilitate these research goals in future. These services will continue to be provided in close integration with the Genomics and Bioinformatics and the Transgenic Mouse Cores. This centralized pathology review of tissues will help place the scientific molecular experiments in context with morphologic neoplastic progression, allowing direct comparison between models and with human prostatic carcinogenesis.